Various theories have been proposed to explain why regeneration of the transected mammalian spinal cord is abortive: Obstruction to the outgrowth of neurities by connective tissue and glial scar, absence of suitable guiding pathways to orient the regenerating nerve fibers, lack of "trophic" influences" sufficient to sustain the regenerative effort, and inhibition of outgrowth as a result of synapse formation have all been suggested as limiting the regenerative potential of spinal neurons. The proposed experiments are designed to evaluate the importance of each of these factors to the process of spinal cord regeneration. The role of scar formation and trophic factors will be evaluated by studies on hibernating animals, in which collagen production is reduced but neurotrophic regulations persist. The role of glial proliferation and its effect on neural function and structure will be assessed by the intrathecal administration of drugs and toxins which selectively affect neural or glial function and structure and by the light and electron microscopical analysis of the early stages of glial proliferation after spinal transection or drug administration. The importance of mechanical guidance and trophic influences will be assessed by experiments on which grafts of neural and other tissues are placed between the cut ends of the transected spinal cord. The role of synaptic or ("contact") inhibition of regeneration will be evaluated by the electron microscopical examination of the region of the spinal cord adjacent to injury in all of the aforementioned experiments. By means of these studies we are seeking ways to achieve improved treatment and to restore function in human paraplegia.